Daniel Neff, Frank Ruschitzka, Martin Hersberger, Frank Enseleit, David Hürlimann, Georg Noll, Thomas Lüscher, Edgar Hänseler
Detection of a Novel Exon 4 Low-Density
Lipoprotein Receptor Gene Deletion in a
Swiss Family with Severe Familial
Hypercholesterolemia
Familial hypercholesterolemia (FH) is an autosomal
dominant disease which results in 2-3-fold elevated
cholesterol levels and in accelerated atherosclerosis. FH
is caused by small mutations or larger rearrangements
in the low-density lipoprotein receptor (LDLR). Here, we
report that screening the LDLR gene in a Swiss family
(n = 15) with clinical symptoms of FH by combined single
strand conformation polymorphism and long-distance
PCR identified a novel 1.3 kb deletion in the LDLR.
The deletion eliminated exon 4 of the LDLR presumably
by recombination between two identical 25 bp repeats
present in intron 3 and 4. The 25 bp sequence in intron 3
is part of an Alu repeat, whereas no homology to Alu repeats
was found for the intron 4 region. This 1.3 kb LDLR
deletion allele cosegregated with elevated cholesterol
levels over three generations. Even on high-dose statin
therapy, carriers of the deletion averaged 1.6 times
higher cholesterol levels and 1.9 times higher apolipoprotein
B-100 (apoB-100) levels than non-carriers
who had lipid and apoB-100 levels within the range of
the Swiss population. Most affected members of the
first and second generation of this family had experienced
a first myocardial infarction (MI) before the age of
55 years and most LDLR gene deletion carriers older
than 40 years showed severe coronary artery disease
(CAD). Hence, we conclude that deletion of exon 4 in the
LDLR gene drastically decreases low-density lipoprotein
binding leading to severe hypercholesterolemia.
Clinical Chemical Laboratory Medicine, Walter de Gruyter
Print ISSN: 1434-6621
Volume: 41, 03/2003
Pages: 266 - 271
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